title: Design, synthesis, and activity of a series of arylpyrid-3-ylmethanones as type I positive allosteric modulators of α7 nicotinic acetylcholine receptors.
abstract: A series of novel arylpyrid-3-ylmethanones (7a-aa) were designed as modulators of α7 nicotinic acetylcholine receptors (nAChRs). The methanones were found to be type I positive allosteric modulators (PAMs) of human α7 nAChRs expressed in Xenopus ooctyes. Structure-activity relationship (SAR) studies resulted in the identification of compound 7v as a potent and efficacious type I PAM with maximum modulation of a nicotine EC5 response of 1200% and EC50 = 0.18 μM. Compound 7z was active in reversing the effect of scopolamine in the novel object recognition (NOR) paradigm with a minimum effective ip dose of 1.0 mg/kg (2.7 μmol/kg). This effect was blocked by the selective α7 nAChR antagonist methyllycaconitine (MLA). These compounds are potent type I positive allosteric modulators of α7 nAChRs that may have therapeutic value in restoring impaired sensory gating and cognitive deficits in schizophrenia and Alzheimer's disease.
authors.affiliation: Department of Pharmacology, College of Medicine, University of California, Irvine , Med Surge 2, Room 372, Irvine, California 92697, United States.
authors.forename: Derk J
authors.initials: DJ
authors.lastname: Hogenkamp
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Ford-Hutchinson
authors.forename: Wen-Yen
authors.initials: WY
authors.lastname: Li
authors.forename: Edward R
authors.initials: ER
authors.lastname: Whittemore
authors.forename: Ryan F
authors.initials: RF
authors.lastname: Yoshimura
authors.forename: Minhtam B
authors.initials: MB
authors.lastname: Tran
authors.forename: Timothy B C
authors.initials: TB
authors.lastname: Johnstone
authors.forename: Gavin D
authors.initials: GD
authors.lastname: Bascom
authors.forename: Hannah
authors.initials: H
authors.lastname: Rollins
authors.forename: Lena
authors.initials: L
authors.lastname: Lu
authors.forename: Kelvin W
authors.initials: KW
authors.lastname: Gee
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D009865:Oocytes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014981:Xenopus; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D011725:Pyridines; D064569:alpha7 Nicotinic Acetylcholine Receptor